Understanding Pain in hEDS

See below for Low-Dose Naltrexone

Pain is one of the most common and complex symptoms in people living with hypermobile Ehlers-Danlos syndrome (hEDS). Studies show that over 80–90% of individuals experience chronic pain, often beginning in childhood with a mean onset around age ten and becoming persistent by early adulthood. For many, pain is one of the earliest and most disabling features of the condition. It can affect almost every part of the body and often interferes with daily activities, emotional well-being, and overall quality of life. Unlike acute pain caused by injury or illness, pain in hEDS tends to be chronic, multifactorial, and resistant to a one-size-fits-all approach. Both degenerative arthritis, which may occur earlier than in the general population, and underrecognized inflammatory arthritis can add to the overall burden of pain.

Sources of Pain in hEDS

Because pain in hEDS arises from many overlapping mechanisms, it helps to consider the major categories of pain separately—while keeping in mind that most people experience several of these at once.

Musculoskeletal Pain

• Due to joint hypermobility, ligaments and tendons can’t support the joints properly. This leads to

  • Recurrent subluxations or dislocations

  • Soft tissue injury

  • Muscle overuse and joint instability during daily movement

• Most people with hEDS experience joint pain. Large studies show nearly all adults and about half of children present with musculoskeletal pain, often in the knees, back, and shoulders.

• Arthritis

  • Osteoarthritis (OA) can occur earlier than usual in hEDS, especially in the knees, hips, spine, and TMJ (temporomandibular joint), likely due to instability and mechanical stress.

  • Inflammatory arthritis (RA, spondyloarthritis) is also more common than in the general population, though often underrecognized without rheumatologic workup.

• Activity limitation and fatigue

Myofascial Pain

• This type of pain originates in muscles and surrounding tissues. It often involves

  • Trigger points (painful muscle knots)

  • Muscle spasms caused by instability or compensation for weak joints

• High prevalence, often overlapping with musculoskeletal pain

Neuropathic Pain

Some people with hEDS experience pain described as burning, tingling, electric-like, or sharply stabbing. Neuropathic pain may involve:

• Peripheral nerve damage or compression, occurring when unstable joints irritate or press on nearby nerves

  • Pain may feel like shooting zaps, sudden jolts of electricity, or a deep ache following the path of the affected nerve

  • Numbness, tingling, or muscle weakness may accompany the pain

• Small fiber neuropathy (SFN), a condition involving degeneration of small nerve fibers

  • Clinical findings include reduced intraepidermal nerve fiber density

  • Symptoms may include:

    • Sharp, shooting, or burning sensations

    • Random or multifocal nerve pain

    • Entrapment and peripheral neuropathies, especially around unstable joints

    • Altered sensory thresholds in painful joints

• Sharp, random nerve pain at unpredictable points on the body, often independent of injury

Additional clinical findings include:

• Prevalence of SFN in ~50–60% of hEDS patients tested

• Surveys showing neuropathic pain in ~30–40% of patients

• Frequent underdiagnosis, since EMGs (electromyography tests that measure electrical activity of muscles and large nerve fibers) may appear normal even when SFN is present

The GeneReviews guideline by the University of Washington notes that chronic pain in hEDS is often neuropathic in nature and that peripheral neuropathies are a frequent contributor.

Central Sensitization

Over time, chronic pain can cause the brain and spinal cord to become oversensitive to pain signals. This process can lead to

• Widespread pain throughout multiple regions of the body, often diffuse, persistent, and shifting in location

• Exaggerated responses to touch or pressure

• Fibromyalgia-like symptoms, including:

  • Widespread musculoskeletal pain

  • Fatigue, even after rest

  • Non-restorative sleep and other sleep disturbances

  • Cognitive issues (“brain fog”) such as trouble concentrating or memory lapses

  • Increased sensitivity to touch, pressure, cold, or noise

  • Tender points or areas unusually sensitive to pressure

• Amplification of peripheral pain signals, such as those from nerve injury or joint instability

• Unpredictable pain distribution, with sharp pain sometimes occurring in unrelated or uninjured areas

Additional clinical findings include

• High prevalence, with up to 90% of hEDS patients in some cohorts reporting central sensitization features or meeting fibromyalgia criteria

• Strong association with disability and fatigue

Central sensitization is believed to be a major factor in hEDS-related pain and may explain why many patients experience both nerve-related and widespread pain symptoms.

Headache Pain

People with hEDS often report multiple forms of headache pain, including:

• Tension-type headaches

• Migraines, sometimes related to cervical spine instability

• Sinus headaches, associated with:

  • Mast cell activation syndrome (MCAS)

  • Allergies

  • Structural contributors such as chronic sinus infections, poor sinus drainage, nasal valve collapse, or deviated septum

• Cervicogenic headaches, arising from cervical spine or TMJ involvement

• Headaches associated with dysautonomia (especially POTS) and neurovascular sensitivity, which can heighten pain perception and vascular congestion, worsening sinus pressure and headache symptoms

Additional clinical findings include:

• High prevalence of migraine, affecting ~40–60% of hEDS patients, compared to ~12–15% in the general population

• Classification as one of the top five disabling pain complaints in hEDS

Visceral Pain

• Visceral pain can come from several sources

  • GI disorders (IBS, reflux, bloating, gastroparesis)

  • Pelvic pain

  • Bladder dysfunction

  • Other sources

• Reported by ~70–80% of patients, with pelvic pain affecting ~50% of women

• Visceral pain often correlates with reduced quality of life as strongly as musculoskeletal pain

Other Contributors

• The following symptoms can worsen pain experience

  • Fatigue

  • Sleep disturbances

  • Anxiety

  • Depression

• Anxiety and depression affect ~40–50% of hEDS patients; sleep disturbance is reported in ~70%.

• These do not cause pain directly but amplify its impact

Possible Treatments for Pain in hEDS

Treating pain in hEDS is often challenging and requires a personalized, multidisciplinary approach. Given the wide range of pain types and mechanisms, no single treatment is sufficient. Instead, care usually involves combining multiple approaches that target different aspects of pain and its impact on daily life.

Physical and Occupational Therapy

This is a cornerstone of hEDS treatment. Therapies may include

• Core strengthening

• Proprioception training

• Joint stabilization exercises

These therapies help improve function and prevent further injury.

Bracing and Assistive Devices

Helpful for preventing injury and supporting unstable joints. This may include

• Splints (medical devices used to support, stabilize, or protect joints and soft tissues)

  • finger

  • thumb

  • wrist

  • ankle

  • knee

  • custom

• Orthotics (custom-made or pre-fabricated medical devices worn inside shoes)

• Braces (medical device designed to support, stabilize, protect, or restrict movement in a joint or body part - less rigid than a splint)

  • knee

  • neck

  • wrist

  • thumb

  • elbow

  • ankle

  • torso/rib

  • back/pelvis

• Mobility aids

  • canes

  • crutches

  • walkers

  • wheelchairs

  • scooters

Medications

Although medications rarely eliminate the pain entirely, they can help manage symptoms

• Non-steroidal anti-inflammatory (NSAID) medications (both prescription and OTC) and acetaminophen for inflammation or injury

• Neuropathic agents (e.g., duloxetine, gabapentin, amitriptyline) for nerve-related or widespread pain

• Muscle relaxants – occasionally used for acute muscle spasm; some may be used daily under supervision, but long-term use is limited by side effects and risk of tolerance

• Opioids – reserved for severe, refractory pain, due to the risks of side effects and dependency

• Low-dose naltrexone (LDN) – showing promise in fibromyalgia and chronic pain (see below)

Behavioral and Psychological Therapies

These therapies help patients manage the emotional and neurological aspects of pain.

• Cognitive Behavioral Therapy (CBT)

• Pain education

• Strategies for stress reduction, sleep, and emotional regulation

Complementary Therapies

Many patients report benefit from

• Acupuncture

• Saline trigger point injections: Saline trigger point injections are sterile saltwater injections into painful muscle knots to relieve tension and pain.

• Massage

• TENS (transcutaneous electrical nerve stimulation)

Surgical Interventions

Sometimes surgery is needed for severe joint instability, but

• Results are often mixed.

• Surgery is only recommended after other treatments fail because hEDS involves fragile tissues and higher complication risks.

Experimental or Theoretical Options

 These treatments lack strong evidence but are being explored

• Prolotherapy: Injections of dextrose or irritants to stimulate tissue repair

• Laser therapy: Low-level laser therapy (LLLT) for inflammation and healing

• Medical marijuana or CBD: Used anecdotally for pain, sleep, and nausea relief

• Suzetrigine (VX-548): A novel drug that blocks peripheral Nav1.8 sodium channel

  • May help with

    • Neuropathic pain

    • Myofascial or soft tissue pain

    • Musculoskeletal pain from subluxations

  • Limitations include lack of evidence in hEDS and limited benefit for central sensitization

Causes and Treatments for Pain

Pain Management Tools for Chronic Conditions

While not hEDS-specific, these evidence-based tools offer helpful strategies.

• Tame the Beast – Educational pain neuroscience videos

• Pathways Pain Relief – A guided app using CBT and mindfulness for chronic pain

• Curable – App combining education, journaling, meditation, and CBT-based pain approaches

Summary

Pain in hypermobile Ehlers-Danlos syndrome (hEDS) is widespread, chronic, and often difficult to manage. Nearly all individuals experience it, frequently starting in childhood and progressing to disabling levels by early adulthood. Arthritis, both degenerative and inflammatory, is more common in hEDS and often appears earlier than in the general population, compounding the effects of joint instability and soft tissue injury. At the same time, neuropathic pain, central sensitization, headaches, visceral pain, and myofascial pain often overlap, so that most patients live with multiple pain types simultaneously. These symptoms are further amplified by fatigue, poor sleep, anxiety, and depression, which increase pain sensitivity and reduce coping ability.

Effective management requires a personalized and multidisciplinary approach. Core treatments include physical and occupational therapy, joint bracing and assistive devices, and medications for nerve and muscle pain. Psychological support and behavioral therapies help address the emotional and neurological aspects of pain, while complementary and integrative options such as massage, acupuncture, and low-dose naltrexone may provide additional relief. Surgery is considered cautiously, and experimental therapies are under investigation but not yet well established in hEDS. Because pain in hEDS is complex and multifactorial, care must be holistic, flexible, and centered on the individual, with the goal of reducing pain, improving function, and supporting quality of life.

Low-Dose Naltrexone (LDN)

Low-dose naltrexone (LDN) is an emerging off-label option for people with widespread pain, fatigue, and central sensitization—features common in hEDS.

What is it?

• A very low dose (1.5–4.5 mg) of the drug naltrexone, traditionally used in much higher doses for opioid or alcohol dependence.

• In low doses, it works very differently, modulating pain and inflammation through unique mechanisms.

• Must be obtained at a compounding pharmacy.

• Often is not covered by insurance due to being prescribed off-label. Off-label prescribing is when a healthcare provider prescribes a medication for a use, dose, or population that is not specifically approved by the FDA but is supported by clinical judgment or evidence from research.

How might it help in hEDS?

• LDN is not a standard therapy for hEDS, but it is increasingly used off-label for chronic pain conditions involving central sensitization, such as fibromyalgia, which shares overlapping features with hEDS.

• Proposed mechanisms

  • Inhibition of microglial activation in the central nervous system

  • Toll-like receptor 4 (TLR4) antagonism

  • Reduction of neuroinflammation, possibly helping to dampen pain amplification and brain fog

• Patients often report improvements in

  • Chronic widespread pain

  • Fatigue

  • Sleep quality

  • Cognitive clarity

Evidence base

• Evidence for LDN in hEDS specifically is limited to anecdotal reports and clinician experience.

• However, systematic reviews and meta-analyses show modest benefit in fibromyalgia and related centralized pain conditions, with a good safety profile.

• Most published studies are small or preliminary; high-quality randomized controlled trials in hEDS are currently lacking.

Tolerability

• LDN is generally well-tolerated.

• May have mild and temporary side effects such as vivid dreams or sleep disruption early on.

Formulations

Because commercial manufacturers do not produce tablets in low doses, LDN must be specially prepared by compounding pharmacies. Common formulations include

• Capsules – The most typical option, often filled with microcrystalline cellulose or another neutral filler. Available in precise strengths (e.g., 1.5 mg, 3 mg, 4.5 mg).

• Tablets – Less commonly compounded but sometimes preferred for patients who have trouble swallowing capsules.

• Liquid formulations – Useful for those who require very gradual dose titration (e.g., starting below 1 mg and increasing slowly). Allows for flexible adjustment in 0.1–0.5 mg increments.

• Sublingual drops or lozenges – Occasionally used when gastrointestinal absorption is a concern, though less standardized.

• Topical creams – An experimental option prepared by some pharmacies, typically for patients who cannot tolerate oral forms; evidence is minimal.

Because inactive ingredients vary between pharmacies, patients with sensitivities to dyes, fillers, or excipients (inactive ingredients) may need to request specific formulations. Prescribers can work with the compounding pharmacist to adjust both dosage and formulation to the patient’s needs.

Insurance and Prescription Access

• Insurance coverage is inconsistent. Many insurers consider LDN experimental or non-essential due to its off-label use and will not reimburse for compounded versions.

• Prior authorization or appeal letters from a provider may be required for coverage, and even then, success varies by plan.

• Compounding pharmacies are typically required because low-dose tablets are not commercially manufactured. Prices can range from $30–90/month depending on formulation and location.

• Patients should

  • Ask whether their prescriber can fax the prescription directly to a known compounding pharmacy.

  • Inquire about discount programs or bulk pricing through pharmacies.

  • Save receipts for out-of-pocket costs, which may be reimbursable through FSA/HSA accounts.

• Some patients also find better prices at online or mail-order compounding pharmacies, though quality and licensing should be verified.